The ultimate objective of the proposed research is to characterize and quantify basic cellular electrophysiological properties of the developing myocardium. It is hoped that an analysis of this information will provide an understanding of the dynamic relationship between the maturation of cardiac cellular processes and the development of clinically significant cardiac arrhythmias in the pediatric population. A comprehensive study of the changes in cellular membrane currents, ionic fluxes, and excitation-contraction coupling processes that accompany growth appears to be a prerequisite to an understanding of the differences in the cellular electrophysiologic properties of neonatal and adult hearts. Although there is evidence suggesting that certain intrinsic electrophysiological and mechanical properties of heart muscle may be age-dependent, many difficulties have surrounded efforts to quantitatively analyze these properties. These problems have arisen because of the technical complexity of adapting standard quantiative electrophysiological techniques to the smaller, more fragile neonatal tissue. However, it now appears that newer methods of examining isolated heart muscle may obviate the technical difficulties that surrounded previous efforts and may be expected to provide comprehensive, quantitative data and meaningful comparisons of neonatal and adult cardiac tissues. The proposed investigation will utilize the voltage clamp technique and ion-sensitive microelectrodes in isolated papillary and septal myocardial preparations to quantitatively elucidate developmental changes in cellular electrophysiological phenomena such as membrane currents, mechanical function, and ionic fluxes. Furthermore, a study will be undertaken of the age-related changes in the response of these variables to clinically relevant stimuli such as hypoxia, ischemia, acidosis and to a variety of antiarrhythmic agents. Integration of this data will provide insight into the mechanisms of generation of arrhythmias in the immature heart, the cellular electrophysiological effects of pathological conditions which predispose to the development of arrhythmias, and the underlying cellular mechanisms of action of common antiarrhythmic agents.